Considerable evidence suggests that neural pathways may modulate cerebral blood flow. Our laboratory has defined one such pathway, which provides parasympathetic innervation to cerebral vessels. We have shown that activation of the pathway produces cerebral vasodilatation while interruption of the pathway counters vasodilatation that normally occurs during acute hypertension. Others have shown that ganglionic fibers of this pathway synthesize and release nitric oxide onto cerebral vessels and we have shown that nitric oxide from the pathway elicits cerebral vasodilatation. Interrupting parasympathetic nerves in this pathway leads to significantly greater volumes of damage to the brain during cerebral ischemia and electrically stimulating the pathway reduces damage from stroke. The hypothesis we test here is that upregulation of neuronal nitric oxide synthase in the parasympathetic ganglionic nerves will attenuate infarct volume and will provide long-lasting neuroprotection from stroke. Our laboratory is well poised to pursue this hypothesis in its having developed molecular tools to do so and in having developed strong preliminary evidence that supports the hypothesis. Neurally mediated protection from stroke has been reported with direct stimulation of deep brain nuclei but that approach requires either invasive surgery or stereotactic placement of stimulating electrodes into the brain in patients who have sustained a stroke. The approach that would be made feasible by the proposed studies could afford similar protection but through an approach that would be minimally invasive and holds promise to reduce infarct burden to affected patients thus reducing costs and intensity of rehabilitation and overall costs to society. Establishing that upregulation of neurotransmission in the parasympathetic innervation of cerebral vessels may reduce damage produced by cerebral ischemia would provide a novel means of complementing existing therapeutic approaches to the treatment of stroke. Those approaches are limited in their efficacy and in the window of opportunity for their application. Enhanced synthesis of responsible transmitters and attendant reduction in infarct volume would be directly applicable in the aging Veteran population, which carries increased risk of stroke. We anticipate that successful results from the proposed studies will lead to translational studies that would include that Veteran population.